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Welcome to Ed's Pathology Notes, placed
here originally for the convenience of medical students
at my school. You need to check the accuracy of any
information, from any source, against other credible
sources. I cannot diagnose or treat over the web,
I cannot comment on the health care you have already
received,
and these notes cannot substitute for your
own doctor's care. I am good at helping people find
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sometimes my E-mail crashes, and sometimes my
literature search software crashes. If you've not heard
from me in a week, post me again. I send my most
challenging questions to the medical student pathology
interest group, minus the name, but with your E-mail
where you can receive a reply.

Numbers in {curly braces} are from the magnificent
Slice
of Life videodisk. No medical student should
be without access to this wonderful resource.

I am presently adding clickable links to
images in these notes. Let me know about good online
sources in addition to these:

Freely have you received, freely give. -- Matthew 10:8. My
site receives an enormous amount of traffic, and I'm
still handling dozens of requests for information weekly, all
as a public service.

Pathology's modern founder,
Rudolf
Virchow M.D., left a legacy
of realism and social conscience for the discipline. I am
a mainstream Christian, a man of science, and a proponent of
common sense and common kindness. I am an outspoken enemy
of all the make-believe and bunk that interfere with
peoples' health, reasonable freedom, and happiness. I
talk and write straight, and without apology.

Throughout these notes, I am speaking only
for myself, and not for any employer, organization,
or associate.

Special thanks to my friend and colleague,
Charles Wheeler M.D.,
pathologist and former Kansas City mayor. Thanks also
to the real Patch
Adams M.D., who wrote me encouragement when we were both
beginning our unusual medical careers.

If you're a private individual who's
enjoyed this site, and want to say, "Thank you, Ed!", then
what I'd like best is a contribution to the Episcopalian home for
abandoned, neglected, and abused kids in Nevada:

Especially if you're looking for
information on a disease with a name
that you know, here are a couple of
great places for you to go right now
and use Medline, which will
allow you to find every relevant
current scientific publication.
You owe it to yourself to learn to
use this invaluable internet resource.
Not only will you find some information
immediately, but you'll have references
to journal articles that you can obtain
by interlibrary loan, plus the names of
the world's foremost experts and their
institutions.

Alternative (complementary) medicine has made real progress since my
generally-unfavorable 1983 review. If you are
interested in complementary medicine, then I would urge you
to visit my new
Alternative Medicine page.
If you are looking for something on complementary
medicine, please go first to
the American
Association of Naturopathic Physicians.
And for your enjoyment... here are some of my old pathology
exams
for medical school undergraduates.

I cannot examine every claim that my correspondents
share with me. Sometimes the independent thinkers
prove to be correct, and paradigms shift as a result.
You also know that extraordinary claims require
extraordinary evidence. When a discovery proves to
square with the observable world, scientists make
reputations by confirming it, and corporations
are soon making profits from it. When a
decades-old claim by a "persecuted genius"
finds no acceptance from mainstream science,
it probably failed some basic experimental tests designed
to eliminate self-deception. If you ask me about
something like this, I will simply invite you to
do some tests yourself, perhaps as a high-school
science project. Who knows? Perhaps
it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship
by suspending their own reasoning and
simply accepting a single authority that seems wise and good.
I've learned that they leave the movements when, and only when, they
discover they have been maliciously deceived.
In the meantime, nothing that I can say or do will
convince such people that I am a decent human being. I no longer
answer my crank mail.

This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.

During the eighteen years my site has been online, it's proved to be
one of the most popular of all internet sites for undergraduate
physician and allied-health education. It is so well-known
that I'm not worried about borrowers.
I never refuse requests from colleagues for permission to
adapt or duplicate it for their own courses... and many do.
So, fellow-teachers,
help yourselves. Don't sell it for a profit, don't use it for a bad purpose,
and at some time in your course, mention me as author and William Carey as my institution. Drop me a note about
your successes. And special
thanks to everyone who's helped and encouraged me, and especially the
people at William Carey
for making it still possible, and my teaching assistants over the years.

Whatever you're looking for on the web, I hope you find it,
here or elsewhere. Health and friendship!

Tell how and when to order a "glucose" on a patient. Give the normal range, and compare "blood"
and "plasma" glucose. Tell how the glucose level changes in a tube of blood as it stands.

Give the NDGG criteria for the diagnosis of diabetes mellitus in the nonpregnant adult. Recognize
causes of secondary glucose intolerance.

Distinguish fasting and postprandial hypoglycemia, and cite causes of each. Be well-informed when
talking with patients and friends about "hypoglycemia", and distinguish true hypoglycemia from
epinephrine-related symptoms.

Explain how to use a blood test to distinguish insulinoma from surreptitious injection of insulin
("factitious hypoglycemia").

Tell what information is provided by the glycosylated hemoglobin assay.

Blood glucose (* dextrose) is one of the most useful and most commonly ordered lab tests. There is
a nice review in Ann. Int. Med. 110: 125, 1989.

Most often, it is performed as part of a profile that also includes sodium, potassium, chloride, total
carbon dioxide content (i.e., approximately the bicarbonate content), urea nitrogen, and usually
creatinine.

Glucose may also be included on the "big" profile that is run on weekday mornings.

In any case, you can always get a stat glucose.

Glucose is most often measured in venous serum.

Normal range for a fasting adult is around 70-105 mg/dL.

Whole blood glucose is around 5-10% lower than serum glucose.

This is because glucose passes freely in and out of the red blood cells, which have a lower content of
water than plasma does (why?).

Capillary blood (as from a finger-stick, essentially arterial blood) usually has around 5 mg/dL more
glucose than venous blood.

After carbohydrate loading (as during a glucose tolerance test), this difference may increase to 20-70 mg/dL because of
increased glucose utilization by peripheral tissues.

Indications for blood glucose testing are frequently encountered. You need this test for:

*There is also some current interest in hyperglycemic response as a prognostic indicator in
myocardial infarction, etc.: Q.J. Med. 71: 461, 1989

Future neurologists: Hyperglycemia is coming to be recognized as an important cause of seizures
(Epilepsia 32: 315, 1991; Neurology 39: 394, 1989).

Detection and management of all forms of hypoglycemia

"Insulin shock", etc., is a very important cause of convulsions, coma, brain damage (* mechanisms:
Stroke 17: 699, 1986), and death. Hypoglycemia can also simulate a stroke, even producing
hemiplegia (Ann.Neurol. 18: 510, 1985; Stroke 18: 944, 1987;Practitioner 232: 298, 1988). When
you first encounter a patient with coma, draw blood for a glucose level before you administer
intravenous glucose.

Remember that neonatal hypoglycemia is common and devastating (Clin. Perinatol. 13: 351, 1986;
Arch. Dis. Child. 63: 1386, 1988), and * hyperglycemia is coming to be recognized as a major
hazard in very small preemies (J. Ped. 109: 905, 1986).

Consider testing for hypoglycemia in patients who seem to be suffering from anxiety neurosis
(especially if there is sweating, trembling, weakness, changes in consciousness), and in obesity.
Remember that normal glucose in these patients is the usual finding in the popular "hypoglycemia
syndrome", and that these people's sufferings are real. See below.

* METHODOLOGY

Because you will be ordering blood glucose levels so often, you may want to know how they are
determined.

The Folin-Wu technique used whole blood. The protein was removed using tungstic acid. Cupric
ions were added, which were reduced to cuprous ions by dissolved glucose. The cuprous ions gave a
deep blue color with phosphomolybdic acid.

Of course, the test really measured everything that reduced cupric ions. This included glutathione,
uric acid, creatinine, ascorbic acid, and other sugars.

All these substances were called "saccharoids".

The Somogyi-Nelson technique was an improvement that used barium hydroxide and zinc sulfate
to precipitate the proteins. This combination also removed most of the non-sugar "saccharoids",
though ascorbic acid and some uric acid remained. Cuprous ions were generated as in the Folin-Wu
technique, and were visualized with arsenomolybdic acid.

Both Folin-Wu and Somogyi-Nelson are now obsolete.

The use of neocuprione to visualize cuprous ions was an improvement, used on many automated
chemical profilers.

Ferricyanide techniques were based on the ability of glucose to reduce this yellow complex to
colorless ferrocyanide in hot alkaline solution. Again, analytical specificity was a problem.

Ortho-toluidine procedures are still sometimes used. The chemical reacts with aldoses (glucose,
galactose, mannose, also with ascorbic acid) to produce a green color at low pH.

A big problem is that the acid destroys the tubing on the machines.

Glucose oxidase techniques are the most popular today. The enzyme generates hydrogen peroxide
as it oxidizes glucose. An indicator system visualizes hydrogen peroxide.

The technique is essentially free from interference by other compounds. * An "enzyme electrode"
that could be implanted in the body: Anal. Chem. 57: 2351, 1985.

Hexokinase is a reference standard and is sometimes used for routine tests as well. The enzyme
converts glucose to glucose-6-phosphatase, which is then measured by its ability to reduce NADP in
the presence of added G6PD.

*Sooner or later, especially with the emphasis on tight control of diabetics to avoid long-term
complications, the chronic intravascular blood glucose sensor will become a familiar piece of
apparatus as part of the automatic pancreas. For now, read Diabetes 39: 1519, 1990.

INTERPRETATION

Blood glucose levels will decrease at a rate of about 7-10 mg/dL per hour at room temperature
unless the red cells are removed or their enzyme systems inhibited.

Fluoride ion is commonly used for this purpose ("gray top tubes" contain oxalate and fluoride).

Note that, especially in renal failure, extremely high levels of glucose may not produce a diuresis
and thus may not represent an acute emergency. This has only recently become clear. See Arch. Int.
Med. 150: 1982, 1990.

just plain stress (heart attack, pneumonia, stroke; see Stroke 22: 692, 1991). White-jacket
hyperglycemia is real, even when you control for poor home-monitoring technique: Br. Med. J. 305:
1194, 1992. Caveat: "Stress" hyperglycemia in a child is less physiologic and often heralds type I
diabetes (J. Ped. 117: 75, 1990).

post-gastrectomy "dumping syndrome"

(Rapid passage of glucose into the jejunum and bloodstream results in a high blood glucose; this in
turn causes a large insulin response with a subsequent drop in glucose to abnormally low levels. See
below.)

Are you sure you didn't draw the blood sample from just above an intravenous glucose
("D5") infusion?

If the blood glucose exceeds the "renal threshold" (i.e., the ability of the kidney to reabsorb all the
glucose from the glomerular filtrate), glycosuria results.

Typically, a normal person's renal threshold is around 180 mg/dL, and so most normal people never
have glucose in the urine.

*The renal threshold tends to be lower in pregnancy (around 140 mg/dL), and higher in old age and
especially in longstanding diabetes (as high as 250 mg/dL).

Some otherwise healthy people have renal glycosuria because of a low renal threshold.

*These differences between people probably cause much more confusion clinically than do the
analytical problems with the current urine test strips (i.e., false negatives due to ascorbic acid or
ketoacidosis).

and remember "factitious hypoglycemia", due to secret administration of insulin to an
otherwise-healthy person. (* Approach to this relatively common scenario: Ann. Int. Med. 108: 252,
1988; it's more of a challenge if the patient is taking sulfonylureas, and in this case, drug assay will
be most helpful).

Adults suspecting of having fasting hypoglycemia are often admitted to the hospital and given only
water for 72 hours, or until they become symptomatic and a blood glucose determination shows a
low value. (Be careful doing this....)

*A reasonable, cheaper alternative is the old intravenous tolbutamide tolerance test, which is
enjoying a resurgence of interest now that it is reasonably well standardized: Mayo Clin. Proc. 64:
1481, 1989.

Postprandial hypoglycemia occurs 1-5 hours after eating. Criteria vary, and investigating suspected
cases is not so like to turn up"organic disease". Causes include:

"dumping syndrome" (see above)

diabetes mellitus, type II (some cases, in the early stages when there is "too much insulin,
too late", or in the * Somogyi phenomenon)

alcoholics (hypoglycemia can be one factor in the discomfort of a hangover)

"functional hypoglycemia" (well, maybe...)

This entity received tremendous attention in the lay press in the late 1970's, and has been blamed for
most individual and social problems. (* See, for example, Acta Psych. Scand. 69: 445, 1984;
criminologists see J. Am. Diet. Assoc. 85: 361, 1985; Arch. Gen. Psych. 46: 600, 1989 -- I blame
stress hormones for the higher violent recidivism among those with lower glucose nadirs; lawyers
read "Hypoglycemia and criminal responsibility" in Diabet. Med. 3: 470, 1986. You remember
how the San Francisco "Twinkie" murderer escaped justice to the dismay of the same conservatives
and liberals who had....)

When certain people are under stress, they tend to get shaky and sickish a few hours after a big meal.
These people will self-diagnose hypoglycemia, but only about 25% (if that) have low blood glucose
during "attacks".

The real problem with these people seems to be an unusually epinephrine response at the glucose
nadir. Epinephrine, not "low glucose", makes them feel "nervous" and "shaky". See JAMA 251:
612, 1984.

Conversely, real hypoglycemia in the absence of high epinephrine is generally unnoticed by patients,
especially diabetics (Lancet 2: 966, 1987).

Until recently, these patients were given five-hour glucose tolerance tests. This is probably
worthless (South. Med. J. 79: 285, 1986; NEJM 321: 1421, 1989; the latter considered true post-prandial
hypoglycemia to be very rare).

By the way, it is now clear that many people have very low blood glucose levels postprandially
without any subjective symptoms. Conversely, if you give home glucose monitors to patients
suffering from "hypoglycemic symptoms relieved by eating" (and assume they know how to use
them), over years you'll find glucose levels simply aren't lower during "symptoms" (Br. Med. J. 300:
16, 1990).

Appropriate management of these patients is still under discussion.

*Feel free to recommend high-protein, low-carbohydrate, low-caffeine, low-alcohol diets that
popular articles recommend for patients self-diagnosing "hypoglycemia", as this does make most of
them feel better.

Some diabetics have no symptoms at all even at very low glucose levels, and these people may have
underlying catecholamine unresponsiveness (J. Clin. End. Metab. 66: 273, 1988) and/or autonomic
neuropathy (Br. Med. J. 301: 783, 1990).

Serum glucose levels should return to normal by 90-120 minutes. Failure to do so suggests diabetes
mellitus.

This test is of course unaffected by altered GI function. ("Dumping syndrome" and malabsorption
can produce an abnormal oral glucose tolerance test.)

Glucose tolerance tests are not usually necessary to make the diagnosis of diabetes mellitus.

The NDGG criteria, based on epidemiologic studies, allow the diagnosis of diabetes mellitus (with
its prognostic implications) to be made in nonpregnant adults in their usual state of health when any
of the following criteria are present (Diabetes 28: 1039, 1979):

fasting venous plasma glucose over 126 mg/dL (was 140) on two occasions (i.e., there is no need for a
glucose tolerance test in such patients)

sustained elevation of venous plasma glucose during a standard oral glucose tolerance test
on two occasions, with both the 120 minute sample and one other sample over 200 mg/dL.

*Exactly what's the best way to screen for diabetes when you're doing patient care, and when you're
doing epidemiology, is an interesting study. The best I've seen in Arch. Int. Med. 153: 2133, 1993.
Diabetes was diagnosed if glucose was >200 mg/dL 2 hours after a standard glucose load. A HgbA1
level of >7.5% picks up 78% of these, a HgbA1c level of >6.3% picks up 80%, and a fasting blood
glucose level of >123 mg/dL picks up 88%. Even a dipstick for glycosuria will pick up 64%.

*The WHO criteria are a bit different: Diabetes 38: 1630, 1989.

Please do not schedule glucose tolerance tests for patients while they are being treated for acute
myocardial infarction or pneumococcal pneumonia....

Future criteria for the diagnosis of diabetes will take advantage of such long-term indicators of
glucose control as glycosylated hemoglobin (see Br. Med. J. 308: 323, 1994 suggests 7.8% means
diabetes).

* INSULIN TOLERANCE TEST

This test measures the patient's ability to respond to a standard dose of insulin with a drop in blood
glucose.

The patient is prepared as for an oral glucose tolerance test. While fasting, the patient is given
insulin 0.1 U/kg as a bolus.

Blood glucose should decrease to about 50% of the fasting level by 30 minutes, and return to normal
by 90-120 minutes.

A blunted response is also seen in around half of patients with "familial pure depression" and
"bipolar depression" between episodes, and this has been recommended as a procedure to distinguish
these entities from other types of depression (Arch. Gen. Psych. 40: 167, 1983).

In the past decade, measurements of glycosylated hemoglobin("GHb") has come into widespread use
as a measure of long-term diabetic control, its principal indication.

On long-term exposure to glucose, the free amino groups of proteins are slowly and
nonenzymatically glycosylated.

*First, unstable aldimines form. Some of these become stable ketoamines.

"Hemoglobin A1" is any hemoglobin A molecule with a single glucose molecule attached in this
way. Most often, the glucose is attached to the valine at the N-terminal end of the beta chain. The
aldimine form is called pre-Hgb A1c, the ketoamine is Hgb A1c.

While pre-Hgb A1c is labile and reflects blood glucose levels over the previous few hours, Hgb A1c
lasts as long as the red blood cell and reflects blood glucose over the previous several weeks.

In normal people and in well-controlled diabetics, Hgb A1c makes up about 3-6% of total
hemoglobin.

In poorly-controlled diabetics, Hgb A1c may exceed 20% of total hemoglobin. (Today's techniques
remove pre-Hgb A1c, which may make up several additional %).

False increases in measured Hgb A1c may be due to Hgb F or H; false decreases may be due to
Hgb S, E, or E. Levels are also lowered by shortened red cell survival time.

*For reviews of the clinical usefulness of this assay, see Acta Med. Scand. S-671: 47, 1983; NEJM
341: 1984; NEJM 310:384, 1984. Serum fructosamine lets you know about diabetic control over
the previous few hours.

* Glycosylated serum proteins may be measured in various ways ("fructosamine", etc.; see Arch. Dis.
Child. 61: 113, 1986), and might eventually be a useful procedure for monitoring blood glucose
control over shorter time intervals. We are already using fructosamine
as a monitor for week-by-week control.

C-PEPTIDE

This "connecting peptide" fragment of proinsulin is secreted by the beta cell in equimolar amounts
with insulin, and is a good measure of true beta cell activity. (It is cleared only one fifth as rapidly
as insulin.)

In my notes, the most helpful current
journal references are embedded in the text.
Students using these during lecture strongly prefer this.
And because the site is constantly being updated,
numbered endnotes would be unmanageable.
What's available online, and for whom, is always changing.
Most public libraries will be happy to help you get an article
that you need. Good luck on your own searches, and again,
if there is any way in which I can help you, please contact me at
scalpel_blade@yahoo.com.
No texting or chat messages, please. Ordinary e-mails are welcome.
Health and friendship!